Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin.

The airway epithelium is subjected to insults such as cigarette smoke (CS), a primary cause of chronic obstructive pulmonary disease (COPD) and serves as an excellent model to study cell plasticity. Here, we show that both CS-exposed and COPD-patient derived epithelia (CHBE) display quantitative evidence of cellular plasticity, with loss of specialized apical features and a transcriptional profile suggestive of partial epithelial-to-mesenchymal transition (pEMT), albeit with distinct cell motion indicative of cellular unjamming. These injured/diseased cells have an increased fraction of polymerized actin, due to loss of the actin-severing protein cofilin-1. We observed that decreasing polymerized actin restores the jammed state in both CHBE and CS-exposed epithelia, indicating that the fraction of polymerized actin is critical in unjamming the epithelia. Our kinetic energy spectral analysis suggests that loss of cofilin-1 results in unjamming, similar to that seen with both CS exposure and in CHBE cells. The findings suggest that in response to chronic injury, although epithelial cells display evidence of pEMT, their movement is more consistent with cellular unjamming. Inhibitors of actin polymerization rectify the unjamming features of the monolayer. This article has an associated First Person interview with the first author of the paper.

Management of Brain Metastases: A Review of Novel Therapies.

Brain metastases (BMs) represent the most common intracranial tumors in adults, and most commonly originate from lung, followed by breast, melanoma, kidney, and colorectal cancer. Management of BM is individualized based on the size and number of brain metastases, the extent of extracranial disease, the primary tumor subtype, neurological symptoms, and prior lines of therapy. Until recently, treatment strategies were limited to local therapies, like surgical resection and radiotherapy, the latter in the form of whole-brain radiotherapy or stereotactic radiosurgery. The next generation of local strategies includes laser interstitial thermal therapy, magnetic hyperthermic therapy, post-resection brachytherapy, and focused ultrasound. New targeted therapies and immunotherapies with documented intracranial activity have transformed clinical outcomes. Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.

Association between high risk of obstructive sleep apnea and inflammatory markers in a population sample of young and middle-aged adults in the Miami Heart Study.

STUDY OBJECTIVES: There are limited data depicting the association between high risk of OSA and the levels of inflammatory markers in a population-based sample free from CVD. In a large U.S. cohort enriched with a Hispanic population and free of cardiovascular disease (CVD), we aimed to assess the association between high risk of obstructive sleep apnea (OSA) and inflammatory markers. METHODS: We analyzed data for 2359 clinical CVD-free participants from the Miami Heart Study, aged 40-65 (May 2015 - Sept 2018). High risk of OSA included those with a high risk using the Berlin questionnaire. Poisson regression analyses were utilized to examine the associations between high risk of OSA (reference: low risk of OSA) and hs-CRP, IL-6, and TNF-α levels (continuous) in univariate and multivariate models (adjusting for age, sex, race/ethnicity, and BMI, diabetes, hypertension, high cholesterol, and smoking). RESULTS: 552 (28%) participants were categorized as having a high risk of OSA. Patients with a high risk of OSA had higher median values of hs-CRP (2.3 vs. 1.0), IL-6 (1.9 vs. 1.4), and TNF-α (1.2 vs. 1.1) when compared to those with a low risk of OSA (all p < 0.001). When adjusting for age, sex, and race/ethnicity, the mean difference between patients with high and low risk of OSA in hs-CRP was 2.04 (95% CI 1.85, 2.23), and 0.73 (95% CI 0.57, 0.89) in IL-6. These differences were attenuated when further adjusting for CVD risk factors but remained statistically significant for hs-CRP: (0.38, 95% CI 0.21, 0.55). CONCLUSIONS: After accounting for CVD risk factors, individuals at high risk of OSA had significantly higher levels of hs-CRP, suggesting that OSA screening identified subclinical inflammation in this population sample of individuals free of CVD.

Prevalence and outcomes of atrial fibrillation in patients hospitalized with COVID-19.

OBJECTIVE: Atrial fibrillation (AF) is a common arrhythmia in patients at high cardiovascular risk. COVID-19 patients with underlying cardiovascular disease are at increased risk of poor clinical outcomes. In this study, we aimed to determine hospital outcomes among patients admitted with AF and COVID-19 infection. METHODS: We conducted a retrospective analysis using the 2020 California State Inpatient data, including all COVID-19 hospitalizations of individuals aged ≥18. Primary outcomes were in-hospital mortality, prolonged length of stay (above the 75th percentile), vasopressor use, mechanical ventilation, and ICU admission. We compared adverse hospital outcomes between those with and without AF and used multivariable logistic regression to adjust for confounders. RESULTS: This analysis included 94,114 COVID-19 hospitalizations, of which 9391 (10.0%) had AF. Patients with COVID-19 and AF had higher rates of adverse outcomes, including mortality (27.2% vs. 9.6%, p < .001), prolonged length of stay (40.0% vs. 27.1%, p < .001), vasopressor use (4.4% vs. 1.9%, p < .001), mechanical ventilation (19.0% vs. 9.1%, p < .001), and ICU admission (18.4% vs. 8.8%, p < .001) After multivariable adjustment, the odds of adverse outcomes remained significantly higher, including mortality adjusted odds ratio [OR], 2.04, 95% CI: 1.92-2.16), prolonged length of stay (aOR, 1.37, 95% CI: 1.31-1.44), vasopressor use (aOR, 1.98, 95% CI: 1.86-2.11), mechanical ventilation (aOR, 1.95, 95% CI: 1.72-2.20), and ICU admission (aOR, 2.01, 95% CI: 1.88-2.15). CONCLUSION: COVID-19 hospitalized patients frequently have underlying AF, which confers a higher risk of adverse hospital outcomes and mortality, even after adjusting for baseline comorbidities. Heightened awareness is needed in the treatment of hospitalized COVID-19 patients with AF.

Atrial fibrillation (AF) is a common heart rhythm disorder, especially in patients with high cardiovascular risk. This study aimed to investigate the hospital outcomes for patients admitted with both AF and COVID-19. We used data from the California State Inpatient Database for the year 2020, focusing on COVID-19 hospitalizations of adults aged 18 and older. The main outcomes studied were in-hospital death, extended hospital stays, use of vasopressor medications that raise blood pressure, need for mechanical ventilation, and admission to the intensive care unit (ICU). Our results showed that patients with both COVID-19 and AF had significantly worse outcomes compared to those without AF. Specifically, these patients had higher rates of death, extended hospital stays, vasopressor medication use, mechanical ventilation, and ICU admission, even after accounting for other health conditions. The study concludes that hospitalized COVID-19 patients with underlying AF are at a greater risk for severe complications and death. This highlights the need for increased attention and care for COVID-19 patients with AF to improve their hospital outcomes.

Outcomes and Trends of Endoscopic Bariatric Therapies (EBT) Among Minority Populations.

INTRODUCTION: Endoscopic bariatric therapies (EBT) have emerged as effective options for weight loss. While the benefits of EBT have been documented, data regarding such therapies among minority populations remains scant. We aim to investigate EBT trends and outcomes in minority populations. METHODS: Data were extracted from the 2015 to 2019 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Project (MBSAQIP) databases. Intragastric balloon (IGB) and endoscopic sleeve gastroplasty (ESG) cases were identified, and procedure volume assessed by year and race/ethnicity. Measures of interest included year-to-year mortality, surgical complications, and 30-day adverse outcomes. RESULTS: Of 966,646 cases in the MBSAQIP databases, 5209 (0.54%) IGB and ESG cases were included. 10.7% were black, and 81.6% were female patients. Compared to white patients, black and Hispanic patients were younger (p < 0.01) with a higher body mass index (p < 0.001). Mortality (0.03% vs. 0% vs. 0%, p = 0.99), reoperation (1.1% vs. 0.8% vs. 0.6%, p = 0.30), and reintervention (3.9% vs. 3.2% vs. 2.3%, p = 0.09) rates were similar between racial/ethnic cohorts. All complications were similar between racial/ethnic cohorts, except a higher rate of venous thromboembolism, in Hispanic (1.04%, p < 0.01) compared to black (0.18%) and white (0.21%) patients. IGB and ESG were predominantly performed in white and Hispanic patients, respectively. ESG was associated with a higher leak (0.6% vs. 0.02%, p < 0.01) and venous thromboembolism (VTE) (1.0% vs. 0.12%, p < 0.01) rate. CONCLUSION: While EBTs have increased annually, they are performed less in black patients. Future studies are needed to identify access barriers for black patients. They are safely performed with similar outcomes in racial/ethnic cohorts, except for a higher VTE rate in Hispanic patients.

Bispecific Antibodies in Lung Cancer: A State-of-the-Art Review.

Bispecific antibodies have emerged as a promising class of therapeutics in the field of oncology, offering an innovative approach to target cancer cells while sparing healthy tissues. These antibodies are designed to bind two different antigens, enabling them to bridge immune cells with cancer cells, resulting in enhanced tumor cell killing and improved treatment responses. This review article summarizes the current landscape of bispecific antibodies in lung cancer, including their mechanisms of action, clinical development, and potential applications in other solid tumor malignancies. Additionally, the challenges and opportunities associated with their use in the clinic are discussed, along with future directions for research and development in this exciting area of cancer immunotherapy.

The Utility of Bronchoscopy in Hydralazine-Induced ANCA-Associated Vasculitis.

Hydralazine is a vasodilator used for the management of hypertension, heart failure, and hypertensive emergencies in pregnancy. It has been implicated in the causation of drug-induced lupus erythematosus (DLE) and rarely with ANCA-associated vasculitis (AAV), which may present as a pulmonary-renal syndrome and be rapidly fatal. Herein, we describe a case of hydralazine-associated AAV presenting as acute kidney injury with the use of early bronchoalveolar lavage (BAL) with serial aliquots to aid with diagnosis. Our case highlights how, in the correct clinical setting, BAL can act as a rapid diagnostic test to help guide quicker treatment to allow for better patient outcomes.

Atherosclerotic plaque in individuals without known cardiovascular disease but with established obstructive sleep apnea and at high risk of obstructive sleep apnea.

Objectives: In a large U.S. cohort free of CVD evaluated by coronary computed CT angiography, we aimed to assess the association between established / high risk of Obstructive Sleep Apnea (OSA) and coronary plaque. Background: There are limited data available depicting the association between established / high risk of OSA and the presence of coronary plaque in a population-based sample free from CVD. Methods: Cross-sectional data from 2359 participants enrolled in the Miami Heart Study (MiHeart) who underwent coronary CT angiography was used for this study. The Berlin questionnaire was used to stratify patients as having high or low risk of OSA. Multiple multivariable logistic regression analyses were conducted to investigate the association between the risk of developing OSA with the presence, volume, and composition of plaque. Results: According to the Berlin questionnaire, 1559 participants were (66.1%) at low risk of OSA and 800 patients (33.9%) with established / high risk of OSA. Plaque characterization on CCTA revealed a greater incidence of any possible plaque composition in the established / high risk of OSA category (59.6% vs. 43.5%) compared to the low risk of OSA cohort. In logistic regression models, after adjusting for demographics and cardiovascular risk factors, a significant association could still be noted between established / high risk of OSA and any coronary plaque on CCTA (OR=1.31, CI 1.05, 1.63, p = 0.016). Subgroup analysis in the Hispanic population also portrayed a significant association between established / high risk of OSA and the presence of coronary plaque on CCTA (OR = 1.55 CI 1.13, 2.12, p = 0.007). Conclusion: After accounting for CVD risk factors, individuals at established / high risk of OSA have a higher likelihood of the presence of coronary plaque. Future studies should focus on OSA presence or risk, OSA severity, and the longitudinal consequences of coronary atherosclerosis.

Perception of Bariatric Surgery and Endoscopic Bariatric Therapies Among Primary Care Physicians.

INTRODUCTION: In the USA, less than 1% of eligible patients who qualify for bariatric surgery ultimately undergo surgery. Perceptions of endoscopic bariatric therapies (EBTs) for weight management remain unknown. METHODS: A 22-question survey was distributed to primary care physicians (PCPs) across the Mayo Clinic healthcare system. Survey invitations were sent via email, and all surveys were unanimously conducted electronically. RESULTS: A total of 130 PCPs participated in the survey (40% response rate). Twenty-four PCPs were between 20 and 24 years out of training (18.5%), and 71 (54.6%) were female. Most providers had a body mass index (BMI) between 18.5 and 24.9 kg/m2 (n = 62, 47.7%). Among the weight loss options discussed during clinic visits, PCPs discussed lifestyle modification including diet and exercise (n = 129; 99.2%), and 68 PCPs (52.3%) were not aware of EBTs as weight loss interventions. While 46.2% of the PCPs agreed that a bariatric endoscopy is an effective option for weight loss, only 24.6% of PCPs were familiar with the indications for EBTs. Most of the cohort (n = 69, 53.1%) experienced barriers in referring their patients. Moreover, most of the patients referred to bariatric clinics were from PCPs who had a BMI between 18.5 and 24.9 kg/m2 (n = 62, 47.7%) as compared to PCPs with a BMI of 40 kg/m2 and greater (n = 5, 3.8%). CONCLUSIONS: Due to the rise of bariatric therapies in recent years, PCPs are increasingly involved in the referral and management of patients with obesity and obesity-related comorbidities. However, knowledge gaps regarding weight loss options, including EBTs, could limit optimal care to patients desiring medically monitored weight loss.

Novel Therapeutic Approaches in Neoplastic Meningitis.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors.

Prior Tonsillectomy and the Risk of Breast Cancer in Females: A Systematic Review and Meta-analysis.

Background: Exposure to recurrent infections in childhood was linked to an increased risk of cancer in adulthood. There is also evidence that a history of tonsillectomy, a procedure often performed in children with recurrent infections, is linked to an increased risk of leukemia and Hodgkin lymphoma. Tonsillectomy could be directly associated with cancer risk, or it could be a proxy for another risk factor such as recurrent infections and chronic inflammation. Nevertheless, the role of recurrent childhood infections and tonsillectomy on the one hand, and the risk of breast cancer (BC) in adulthood remain understudied. Our study aims to verify whether a history of tonsillectomy increases the risk of BC in women. Methods: A systematic review was performed using PubMed, Google Scholar, Scopus, Embase, and Web of Science databases from inception to January 25, 2022, to identify the studies which assessed the association between the history of tonsillectomy and BC in females. Odds ratio (OR) was calculated using the random/fixed-effects models to synthesize the associations between tonsillectomy and BC risk based on heterogeneity. Results: Eight studies included 2252 patients with breast cancer of which 1151 underwent tonsillectomy and 5314 controls of which 1725 had their tonsils removed. Patients with a history of tonsillectomy showed a higher subsequent risk of developing BC (OR, 1.24; 95% CI: 1.11-1.39) as compared to patients without a history of tonsillectomy. Influence analyses showed that no single study had a significant effect on the overall estimate or the heterogeneity. Conclusions: Our study revealed that a history of tonsillectomy is associated with an increased risk of breast cancer. These findings underscore the need for frequent follow-ups and screening of tonsillectomy patients to assess for the risk of BC.